Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

A. B. D'Assoro, R. Busby, I. D. Acu, C. Quatraro, M. M. Reinholz, D. J. Farrugia, M. A. Schroeder, C. Allen, F. Stivala, E. Galanis, J. L. Salisbury

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

In this study, we establish an MCF-7 xenograft model that mimics the progression of human breast carcinomas typified by loss of p53 integrity, development of centrosome amplification, acquired estrogen receptor (ERα) heterogeneity, overexpression of Mdm2 and metastatic spread from the primary tumor to distant organs. MCF-7 cells with abrogated p53 function (vMCF-7 Dnp53) maintained nuclear ERα expression and normal centrosome characteristics in vitro. However, following mitogen stimulation, they developed centrosome amplification and a higher frequency of aberrant mitotic spindles. Centrosome amplification was dependent on cdk2/cyclin activity since treatment with the small molecule inhibitor SU9516 suppressed centriole reduplication. In contrast to the parental MCF-7 cells, when introduced into nude mice as xenografts, tumors derived from the vMCF-7DNp53 cell line developed a strikingly altered phenotype characterized by increased tumor growth, higher tumor histopathology grade, centrosome amplification, loss of nuclear ERα expression, increased expression of Mdm-2 oncoprotein and resistance to the antiestrogen tamoxifen. Importantly, while MCF-7 xenografts did not develop distant metastases, primary tumors derived from vMCF-7DNp53 cells gave rise to lung metastases. Taken together, these observations indicate that abrogation of p53 function and consequent deregulation of the G1/S cell cycle transition leads to centrosome amplification responsible for breast cancer progression.

Original languageEnglish (US)
Pages (from-to)3901-3911
Number of pages11
JournalOncogene
Volume27
Issue number28
DOIs
StatePublished - Jun 26 2008

Keywords

  • Cell cycle
  • Estrogen independence
  • Mitosis
  • Tumor progression

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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